High Risk ACS: PCI & Real LIFE data EUROVISION registry Martial HAMON, MD, FESC University Hospital of Caen INSERM 744, IPL

EURO-VISION EUROpean biValIrudin utiliSatION in practice Disclosure Statement of Financial Interest ●Grant/Research Support: GlaxoSmithKline, Lilly, The Medicines Company. ●Consulting Fees/Honoraria: Terumo, The Medicines Company, Biotronik, Cordis, Medtronic. Affiliation/Financial Relationship

EURO-VISION EUROpean biValIrudin utiliSatION in practice Real World Studies Premier Perspective Database EUROVISION Diversity across PCI patients BAT ACUITY-PCI REPLACE-2 HORIZONS AMI Meta- analyses Time Clinical data across randomized trials and real world use in PCI Bivalirudin: direct thrombin inhibitor

EURO-VISION EUROpean biValIrudin utiliSatION in practice Central Role of Thrombin in Thrombosis Rupture, Erosion, Fissuration Hoffman et al Thromb Haemost Becker R. Am Heart J Initiation: Tissue factor 2.Amplification: Platelets Thrombin platelet activation 3.Propagation Massive thrombin production Adapted from Mann K et al. Arterioscler Thromb Vasc Biol Coughlin S et al. Thromb Haem Thrombin Generation in Thrombosis Clot Time 4.7 ± 0.2 Initiation Threshold of Amplification Propagation >96% of thrombin produced after the clot is seen Time (min) Thrombin-antithrombin complex (nM) ,000 Whole blood from 35 healthy volunteers, tissue factor and phospholipid added to induce clotting

EURO-VISION EUROpean biValIrudin utiliSatION in practice ADP + T X A 2 Neutrophils Monocytes Activated platelets Endothelial cells Activated platelets Resting platelets Monocyte Resting platelets II Tenase complex Thrombin Prothrombin Prothrombinase complex TF Activated platelets Fibrin THROMBIN Croce K et al. Curr Opin Hematol Coughlin SR. Nature. 200 Mann KG. Chest Monroe DM et al. ATVBiol The critical roles of thrombin

EURO-VISION EUROpean biValIrudin utiliSatION in practice 2 1 Antithrombin Thrombin Antithrombin Heparin Pentasaccharide sequence Antithrombin Factor Xa LMWH Pentasaccharide sequence Heparin chains with pentasaccharide sequence (~30%) bind to AT causing a conformational change Thrombin inhibition requires “bridging” by heparin chain (at least 18 units) LMWH has greater activity against Xa than thrombin Heparin/LMWH: mechanism of action Hirsh J et al. Chest. 2001; 119:64S–94S Adapted from Weitz JI et al. J Clin Invest. 1990;86:388. Heparin concentration (units/mL) Inhibition (%) Soluble thrombinClot-bound thrombin Weitz JI et al. J Clin Invest  Unpredictable anticoagulant response  Narrow therapeutic window  Limited activity in the presence of platelet-rich clot  Procoagulant effect (Heparin-induced platelet activation)  Heparin-induced thrombocytopenia (Heparin-PF4 Ab) Heparin Limitations Hirsh J et al. Chest. 1995; Weitz JI et al. Circulation. 2002; Hirsh J et al. Chest. 1998; Sobel M et al. J Vasc Surg. 2001; Anand SX et al. Am J Cardiol

EURO-VISION EUROpean biValIrudin utiliSatION in practice Time (min:sec) Time (min:sec) Time (min:sec) Platelet aggregation (%) Granule secretion 2 µM ADP +3 µM/ml Fond. ADP 2 µM NaCl LMWH 0.2U/ml LMWH + ADP ADP UFH + ADP ADP UFH + ADP ADP Heparin or NaCl ADP 2 µM These agents bind directly to and activate the GP IIb/IIIa receptor Platelet activation increased With UFH, LMWH, Fondaparinux Ex vivo data based on human platelet -rich plasma; concentrations of heparin used were 0.1 to 1 U/mL, to simulate therapeutic range; similar concentrations of LMWH and fondaparinux used. Adapted from Gao C. et al and supplemental data Blood 2011; 117(18):

EURO-VISION EUROpean biValIrudin utiliSatION in practice Bivalirudin mechanism of action (Gly) 4 D-Phe-Pro-Arg-Pro (active-site-binding portion) C-terminal dodecapeptide (Substrate recognition: Exosite 1-binding portion) Bivalirudin binds to active site and substrate recognition site of thrombin Bivalirudin slowly cleaved allowing thrombin to resume its hemostatic function Maraganore J et al Biochemistry 1990;30: Direct and reversible binding to thrombin Thrombin PCI Dose Initial Dose Mean Plasma Conc. (mcg/mL) Elapsed Time From Start of Bivalirudin Bolus (Hours) BBBIII 0.75 mg/kg bolus B mg/kg/h infusion I * 2 Initial 0.1 mg/kg B mg/kg/h I ; At the time of PCI 0.5 mg/kg B mg/kg/h I †3 Shown to provide adequate anticoagulation in PCI (6.5 mcg/mL) 4 = 25-minutes half-life †Dose used in the ACUITY trial. PCI dose derived from phase 2 dose ranging study used in REPLACE-1 & 2. 2 Lincoff AM et al. JAMA 2003; 289: Stone G et al. Am Heart J. 2004;148: Topol E, et al. Circulation 1993; 87:1622. Bivalirudin: predictable pharmacology

EURO-VISION EUROpean biValIrudin utiliSatION in practice Bivalirudin: Platelet inhibition via thrombin Thrombin is the most potent platelet agonist known Coughlin SR, Nature 2000 Weitz J, et al. Am J Cardiol Anand SX et al. Am J Cardiol Control platelets Platelets treated with UFH Platelets treated with Bivalirudin Platelets from healthy volunteers treated with 30 min bivalirudin (12μg/mL) or 0.1 to 1.0 U/mL of heparin Schneider et al Cor Ar Dis 2006 UFH 1.2 U/mL UFH 2 U/mL UFH + Eptifibatide Bivalirudin % of platelets expressing p-selectin % of Activated Platelets % of platelets binding PAC-1 Thrombin U/mL

EURO-VISION EUROpean biValIrudin utiliSatION in practice *Ischemic endpoints: death, MI, and revascularization REPLACE-2 1 N=6,002 UFH +GP IIb/IIIa vs Bivalirudin (Urgent/elective PCI) ACUITY 2 N=9,215 UFH + GPIIb/IIIa vs Bivalirudin (ACS) HORIZONS-AMI 3 N=3,602 UFH ± GP IIb/IIIa vs Bivalirudin (primary PCI) Heparin + GP IIb/IIIa Bivalirudin IschemiaBleeding IschemiaBleeding IschemiaBleeding 7.3% 5.7% 3.0% 7.8% 0% 2% 4% 6% 8% 10% P=.32 P< % 4.2% 2.4% 7.0% 0% 2% 4% 6% 8% 10% P=.23 P< % 8.3% 4.9% 5.4% 0% 2% 4% 6% 8% 10% P=.95 P< day events (%) Bivalirudin Trials Ischemic and Bleeding Outcomes Lincoff AM et al. JAMA. 2003;289: Stone GW et al. NEJM. 2006;355: Stone GW. NEJM 2008;358:

EURO-VISION EUROpean biValIrudin utiliSatION in practice Cardiac mortality 30 days to 3 years Bivalirudin (n=1800) Heparin + GPIIb/IIIa (n=1802) 30-d † HR [95% CI] 0.62; [0.40,0.96] P = % 2.9%

In hospital and 30 day outcomes in all-comer PCI with Bivalirudin Initial report of the prospective EUROVISION Registry. Hamon M 1, Nienaber C 2, Galli S 3, Huber K 4, Gulba D 5, Hill J 6, Lafont A 7, Cequier A 8, Bernstein D 9, Deliargyris E 9 on Behalf of the Eurovision Investigators 1. Centre Hospitalier Universitaire de Caen, France. 2. Department of Cardiology and Angiology, University Hospital Rostock, Rostock School of Medicine, Rostock, Germany. 3. Department of Cardiovascular Sciences, University of Milan, Centro Cardiologico Monzino, IRCCS, Milan, Italy. 4. Third Department of Medicine, Cardiology and Emergency Medicine, Wilhelminen hospital, Vienna, Austria. 5. Department of Cardiology, Krankenhaus Düren, Düren, Germany. 6. King's College Hospital, King's College, London, UK. 7. Cardiology Department, University Paris-Descartes; AP-HP; European Georges Pompidou Hospital, Paris, France. 8. Hospital de Bellvitge, Barcelona, Spain. 9. The Medicines Company, Parsippany NJ, USA.

EURO-VISION EUROpean biValIrudin utiliSatION in practice 13 ●Purpose: The EUROVISION Registry was designed to capture patterns of bivalirudin utilization and short term outcomes associated with the use of bivalirudin (BIV) during PCI procedures in Europe. ●Methods: consecutive BIV-treated patients included from 58 sites in 5 countries (Germany, Italy, France, Austria, United Kingdom). ●Outcomes: In-hospital and 30-day assessments -Death, MI, stroke and urgent revascularization -major bleeding according to ACUITY definition -and minor bleeding any bleeding not included in the definition of major bleeding Objectives and Methods ● In the ImproveR registry bolus only dosing was observed in EU clinical practice. ● Bolus only dosing was associated with increased in-hospital ischaemic events (MACE) ● The safety and efficacy of a bolus only dose of ANGIOX has not been evaluated and is not recommended even if a short PCI procedure is planned.

EURO-VISION EUROpean biValIrudin utiliSatION in practice Ischaemic events less frequent Ischaemic events more frequent Odds ratio [95% CI] UFH/LMWH <24h after PCI (n=1069) Age >65 years (n=2230) Angiox double bolus (n=268) STEMI (n=407) PCI >45 minutes (n=1074) Coumarins (n=99) GP IIb/IIIa inhibitors (n=179) ImproveR Registry Madsen JK et al. EuroIntervention 2008:3:610-6 ● An observational study of Angiox use in 4552 patients undergoing PCI. – 26.3% of patients received a single bolus dose – no subsequent infusion – 7.1% of patients received a double bolus dose – no subsequent infusion – Bolus only dosing associated with in-hospital ischaemic events (MACE)

EURO-VISION EUROpean biValIrudin utiliSatION in practice Study Population 2018 PCI-patients from 58 sites in 5 European countries French Investigators, Top 12: - Dr Lipiecki (n=96) - Dr Elhadad (n=88) - Pr Paganelli (n=87) - Pr Lafont (n=60) - Dr Hassani (n=36) - Pr Schiele (n=30) - Pr Carrié (n=25) - Dr Caussin (n=21) - Dr Loubeyre (n=18) - Dr Vilarem (n=15) - Dr Dibon (n=15) - Pr Steg (n=9) Top Investigators (n>100): Pr Galli, Dr Goldman, Pr Huber, Dr Helmreich.

EURO-VISION EUROpean biValIrudin utiliSatION in practice Distribution of PCI-patients: Indication Overall, 58% of patients were cardiac marker -positive N=523 N=315 N=499 N=678 - Overall, P2Y 12 inhibitor preloading occurred in 95% of patients - 91% clopidogrel (65% with 600 mg, 33% with 300 mg) and 9% prasugrel - 45% of patients received other antithrombin therapy prior to PCI and were then switched to bivalirudin - Activated clotting time was checked in only 2.8%

EURO-VISION EUROpean biValIrudin utiliSatION in practice n/N Bivalirudin (N=2018) Age (yrs), mean ± SD65.5 ± 11.9 Age >65 yr1122 / % Female499 / % Weight (kg) mean ± SD-79.8 ± 14.9 Prior MI486 / % Dyslipidemia1215 / % Prior PCI636 / % Hypertension1385 / % Previous CABG145 / % Congestive Heart Failure130 / % Current Smoker588 / % Family history of PVD405 / % Diabetes482 / % Baseline characteristics

EURO-VISION EUROpean biValIrudin utiliSatION in practice n/N Bivalirudin (N=2018) # diseased vessels >11086 / % Actual treatment PCI1933 / % Actual treatment CABG13 / % Medical management70 / % Femoral access1353 / % Radial access580 / % Intervention Type: Balloon Angioplasty883 / % Drug-Eluting Stent1219 / % Non drug-Eluting Stent626 / % Procedure duration, mean ±SD36.0 ± 43.6 GP IIb/IIIa use85 / % Procedural characteristics

EURO-VISION EUROpean biValIrudin utiliSatION in practice EUROVISION: 30-day Efficacy outcomes % of Events All patients n=2018

EURO-VISION EUROpean biValIrudin utiliSatION in practice EUROVISION: 30-day Safety outcomes All patients n=2018 % of Events

EURO-VISION EUROpean biValIrudin utiliSatION in practice Overall rate of stent thrombosis 0.3% (6/2018) Stent thrombosis by diagnosis

EURO-VISION EUROpean biValIrudin utiliSatION in practice Deaths at 1 year subsequent to an event UFH + GP IIb/IIIa inhibitorBivalirudin Acute ST (<24 H) Sub-acute ST (24 H to 30 d) Late ST (30 days to 1 y) Protocol Major Bleeding (1 y ) Re-infarction (1 y) Stroke (1 y ) Mortality rate at 1 Year % (n/N) * 4.2% (1/24) 25% (1/4) 15.0% (3/20) 53.3% (16/30) 17.6% (3/17) 27.3% (6/22) 12.6% (13/103) 18.8% (31/165) 8.1% (5/62) 14.5% (11/76) 25% (5/20) 20% (4/20) Event *In this post-hoc analysis, the mortality rate, n/N, is defined as the number of patients, n, who died after 1 year out of the number of patients, N, who had the event per treatment group

EURO-VISION EUROpean biValIrudin utiliSatION in practice Outcomes by post-PCI infusion Bivalirudin post-PCI infusion n=916 Bivalirudin no post-PCI infusion n=1017 Death/ MI/ Stroke/ Revasc2.4%3.3% Death/ MI/ Revasc/ Stroke/ Major Bleed 3.4%5.1% Death0.9%1.2% Stent thrombosis0.4%0.2% Acute0.1% Sub-acute0.3%0.1% Major bleed1.1%2.0% Among STEMI patients, 62% received a post-procedural bivalirudin infusion for a median duration of 122 minutes

EURO-VISION EUROpean biValIrudin utiliSatION in practice EUROVISION: 30-day Diabetes - Efficacy No Diabetes n=1514 Diabetes n=482 % of Events

EURO-VISION EUROpean biValIrudin utiliSatION in practice EUROVISION: 30-day Diabetes - Safety No Diabetes n=1514 Diabetes n=482 % of Events

EURO-VISION EUROpean biValIrudin utiliSatION in practice EUROVISION: 30-day Diabetes - Summary No Diabetes n=1514 Diabetes n=482

EURO-VISION EUROpean biValIrudin utiliSatION in practice Country Bivalirudin Femoral (N=1353) Bivalirudin Radial (N=580) France14.6%62.9% Italy16.0%28.3% Austria21.4%0.7% United Kingdom4.4%3.6% Germany43.5%4.5% Diagnosis Stable Angina29.3%15.5% Unstable Angina14.7%18.1% NSTEMI20.8%33.8% STEMI35.1%32.6% Access route by country and diagnosis

EURO-VISION EUROpean biValIrudin utiliSatION in practice Baseline Characteristics Bivalirudin Femoral (n=1353) Bivalirudin Radial (n=580) p-value Age (yrs), mean ± SD65.7 ± ± 12.2NS Female23.7%24.3%NS Weight (kg) mean ± SD80.0 ± ± 14.9NS Prior MI26.5%19.8%0.003 Dyslipidemia63.3%54.1%< Prior PCI35.3%24.7%< Hypertension72.7%59.5%< Previous CABG8.2%5.0% Congestive Heart Failure8.0%3.4%< Current Smoker29.2%28.8%< Family history of PVD21.5%16.4%< Diabetes24.4%20.9%NS

EURO-VISION EUROpean biValIrudin utiliSatION in practice 30 day Ischemic Outcomes (unadjusted) Femoral (n=1353) Radial (n=580) P-value Death/ MI/ Stroke/ Revasc3.2%2.2% Death/MI/ Revasc/ Stroke/ Major Bleed 4.7%3.3% Death1.1%0.9% MI1.6%0.2% Unplanned revasc0.7%1.4% Stroke0.3%0% Stent thrombosis0.2%0.5% Acute0.1%0.2% Sub-acute0.1%0.3% There were no differences noted in ischemic events at 30 days between the two groups

EURO-VISION EUROpean biValIrudin utiliSatION in practice Bleeding Outcomes (unadjusted) Femoral (n=1353) Radial (n=580) P-value Major Bleeding1.7%1.2% Minor Bleeding4.8%1.9% Thrombocytopenia0% - Access Site Bleed3.6%1.0% Non-Access Site Bleed1.6%0.9%0.1897

EURO-VISION EUROpean biValIrudin utiliSatION in practice Odds Ratio (95% CI) P- value Ischemic events (D/MI/UR/Stroke) Congestive heart failure2.37 [ ]0.011 Major bleeding (ACUITY) Renal impairment3.99 [ ]<0.001 Independent predictors of ischemic events and major bleeding

EURO-VISION EUROpean biValIrudin utiliSatION in practice Odds Ratio (95% CI) P- value Age ≥ [ ]0.013 Hypertension2.86 [ ]0.004 Prior PCI0.58 [ ]0.044 Radial access0.40 [ ]0.007 Independent predictors of minor bleeding

EURO-VISION EUROpean biValIrudin utiliSatION in practice CONCLUSION (1) ●Adoption of BIV as the foundation for all-comer PCI including high percentage of STEMI and NSTEMI patients is : -associated with excellent ischemic protection -and unsurpassed safety. ●The use of Bivalirudin negated the risk associated with diabetes ●In the context of bivalirudin monotherapy during PCI, both ischemic and major bleeding complication rates at 30 days were similar irrespective of a femoral versus radial access site choice. ●The choice of radial access, however, was associated with lower rates of both minor and access site bleeding. ●Outcomes at 30 day observed in EUROVISION compare favorably to other large existing registry datasets

EURO-VISION EUROpean biValIrudin utiliSatION in practice ESC/ EACTS 2010 Guidelines for Myocardial Revascularization Wijns et al Eur Heart J Oct;31(20): STEMI ClassLevel IBBivalirudin (monotherapy) ICUFH IIIBFondaparinux NSTE-ACS ClassLevel Very high-risk of ischaemia IBBivalirudin (monotherapy) or ICUFH (+GPIIb-IIIa antagonists) Medium-to-high-risk of ischaemia IBBivalirudin ICUFH IBFondaparinux

EURO-VISION EUROpean biValIrudin utiliSatION in practice High Risk PCI: 1 year mortality /Risk factors REPLACE-2, ACUITY & HORIZONS-AMI (n= 14,258 DAPT) Risk Factors included in the stratification model: 1) Age>65, 2) Diabetes, 3) Hypertension, 4) Creatinine clearance<60mg/mL, 5) LVEF<35%, 6)NSTEMI, 7)STEMI, 8)Previous MI and 9) hematocrit<36.

EURO-VISION EUROpean biValIrudin utiliSatION in practice One year mortality and risk factors Pooled analysis: REPLACE-2, ACUITY & HORIZONS-AMI (n= 14,258 DAPT) † fixed model ‡ random effects model RR (95% CI) P- value REPLACE (0.52,1.09)0.14 ACUITY0.92 (0.70,1.20)0.53 HORIZONS0.67 (0.48, 0.94)0.018 Pooled analysis † 0.80 (0.66, 0.96)0.015 Pooled analysis ‡ 0.79 (0.66, 0.96)0.018 Bivalirudin better UFH/GPIIbIIIa better Pooled analysis, 1-year mortality Risk factor (n / N) RR (95% Cl) P- value Age >65 (314 / 5797)0.79 (0.64, 0.98)0.036 Diabetes (159 / 3598)0.77 (0.57, 1.05)0.097 Hypertension (313 / 9130)0.84 (0.68, 1.05)0.121 CrCl<60 mg/mL (171 / 2370)0.75 (0.56, 1.00)0.049 LVEF <35 (82 / 682)0.47 (0.30, 0.72)  biomarkers (NSTEMI) (139 / 3494)0.91 (0.66, 1.26)0.573 STEMI (135 / 3490)0.67 (0.48, 0.94)0.019 Previous MI (144 / 4088)0.89 (0.64, 1.22)0.463 Hematocrit <36% (102 /1684)0.86 (0.59, 1.25)0.418 Bivalirudin better UFH/GPIIbIIIa better 1-year mortality and subgroup analysis 20% RR Death reduction with BivalirudinConsistent results among subgroups

EURO-VISION EUROpean biValIrudin utiliSatION in practice One year mortality and risk factors REPLACE-2, ACUITY & HORIZONS-AMI (n= 14,258 DAPT) RR (95% CI) P- value 30- day death 0, 1 or 2 risk factors0.87 (0.45, 1.67) or more risk factors0.71 (0.51, 1.00) year death 0, 1 or 2 risk factors0.94 (0.66, 1.35) or more risk factors0.76 (0.61, 0.94) day and 1-year Mortality Low Risk = 8082 High Risk = 6176 Bivalirudin better UFH/GPIIbIIIa better 1-year death (%) Log Rank P-Value: Estimate: Overall: Biv: 4.9% Biv* vs Hep: Hep: 7.1% 1-year mortality, ≥ 3 risk factors (n=6,176) Bivalirudin better in high risk PCI

EURO-VISION EUROpean biValIrudin utiliSatION in practice 1-year mortality, LVEF <35% ● (n=682, overall 1 year mortality rate of 12%) Patients at Risk: Biv Hep % 7.8% p= RR (95% Cl) P-value REPLACE-2 LVEF <35 (N=214) 0.46 (0.19, 1.12) ACUITY LVEF <35 (N=253)0.51 (0.26, 0.99)0.044 HORIZONS LVEF <35 (N=215)0.43 (0.20, 0.91)0.022 Pooled LVEF <35 (N=682) 0.47 (0.30, 0.72) REPLACE-2 LVEF ≥35 (N=3703) 0.85 (0.53, 1.37)0.499 ACUITY LVEF ≥35 (N=3499)1.06 (0.74, 1.53)0.739 HORIZONS LVEF ≥35 (N=2744) 0.80 (0.51, 1.24)0.311 Pooled LVEF ≥35 (N=9946)0.92 (0.72, 1.17)0.496 Bivalirudin better UFH/GPIIbIIIa better Consistent effect REPLACE-2, ACUITY, HORIZONS 1-year mortality by LVEF Bivalirudin better in high risk PCI

EURO-VISION EUROpean biValIrudin utiliSatION in practice Risk of Death, MI, Revasc. up to 7-days Pooled meta-analysis Cleveland Clinic F (n=16,519) GPIIb-IIIa with heparin (n=7,629) ≥14,000 U heparin (n=2,151) 7-10,000 U heparin (n=4,578) Angiomax (n=2,161) Risk of TIMI major Bleeding in Hosptial Indirect and unpredictable thrombin inhibition by UFH provides inadequate ischemic protection in high risk ACS Addition of GPI’s improves ischemic protection at the cost of increased bleeding – modest if any mortality benefit Bivalirudin trials have consistently demonstrated equivalent efficacy to GPI+UFH with reduced bleeding Progress in High Risk ACS/PCI Conclusion (2)

EURO-VISION EUROpean biValIrudin utiliSatION in practice ESC/ EACTS 2010 Guidelines for Myocardial Revascularization Wijns et al Eur Heart J Oct;31(20): STEMI ClassLevel IBBivalirudin (monotherapy) ICUFH IIIBFondaparinux NSTE-ACS ClassLevel Very high-risk of ischaemia IBBivalirudin (monotherapy) or ICUFH (+GPIIb-IIIa antagonists) Medium-to-high-risk of ischaemia IBBivalirudin ICUFH IBFondaparinux

EURO-VISION EUROpean biValIrudin utiliSatION in practice THANK YOU FOR YOUR ATTENTION

EURO-VISION EUROpean biValIrudin utiliSatION in practice Bleeding Risk: Access and non-access bleeding Jolly S et al Lancet 2011;377: RIVAL Trial PCI-patients randomized to radial or femoral access, N=7021 Sources and incidence of bleeding Pooled analysis REPLACE-2, ACUITY-PCI, HORIZONS-AMI: N=17, % (n=925) Non- access site 61.4% (n=568) Access site only 38.6% (n=375) Verheugt JACC Cardio Interv 2011;4: % 2.1% Hazard ratio Access site 1.82 (1.17– 2.83) Non-access site 3.94 (3.07– 5.15) < No BleedTIMI Major + Minor Bleed 1-year (adjusted) mortality hazard bleeding vs no bleeding 1-year mortality risk non-access site vs access site bleeding HR 2.27 (95%CI ), p=0.0007

EURO-VISION EUROpean biValIrudin utiliSatION in practice Bleeding Risk / Pharmacotherapy strategy TIMI Major + Minor BleedingRelative RiskP-Value Access only0.45 ( )< All non-access0.62 ( )< Both0.31 ( )< Non-access only0.70 ( )0.08 Indeterminate0.75 ( )0.02 Bivalirudin better Hep + GPI better Verheugt JACC Cardio Interv 2011;4:191-7 Relative risk of bleeding by treatment Pooled analysis REPLACE-2, ACUITY-PCI, HORIZONS-AMI, N=17,393 Bleeding Risk Access/Pharmacotherapy By bleeding risk category (n=982,077) Marso et al. ACC/i2 Scientific Sessions 2010; abstract Low* (<1%) Intermediate* (1-3%) High* (>3%) Overall* MC BV R BR *P<0.001, 4-way comparison MC = Manual compression BV = Bivalirudin R = Radial PCI BR = Bivalirudin + radial P=0.05P=0.06 Records from NCDR Synergistic effect of radial and bivalirudin for reducing major bleeding And subsequent potential deleterious outcomes

EURO-VISION EUROpean biValIrudin utiliSatION in practice Risk of Death, MI, Revasc. up to 7-days Summary results RR (95% CI) GPIIb-IIIa inh. +UFH/LMWH Heparin LMWH Bivalirudin Risk of TIMI major Bleeding in Hosptial Indirect and unpredictable thrombin inhibition by UFH provides inadequate ischemic protection in high risk ACS Addition of GPI’s improves ischemic protection at the cost of increased bleeding – modest if any mortality benefit Bivalirudin trials have consistently demonstrated equivalent efficacy to GPI+UFH with reduced bleeding Progress in High Risk ACS/PCI Conclusion (2)